Tohoku J. Exp. Med., 2019 October, 249(2)

Glomerular Injury Is Exacerbated in Lupus-Prone MRL/lpr Mice Treated with a Protease-Activated Receptor 2 Antagonist

RINA ITTO,¹ YUJI OE,^2,3 KENTA IMARUOKA,¹ EMIKO SATO,^1,4 AKIYO SEKIMOTO,^1,4 SHU YAMAKAGE,⁴ SATOSHI KUMAKURA,⁴ HIROSHI SATO,^1,4 SADAYOSHI ITO⁴ and NOBUYUKI TAKAHASHI^1,4

¹Division of Clinical Pharmacology and Therapeutics, Tohoku University Graduate School of Pharmaceutical Sciences, Sendai, Miyagi, Japan
²Division of Feto-Maternal Medical Science, Department of Community Medical Support, Tohoku Medical Megabank Organization, Tohoku University, Sendai, Miyagi, Japan
³Research Fellow of Japan Society for the Promotion of Science, Tokyo, Japan
⁴Division of Nephrology, Endocrinology, and Vascular Medicine, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan

Systemic lupus erythematosus (SLE) is characterized by the production of autoantibodies, which causes multi-organ injury such as lupus nephritis. SLE is associated with hypercoagulability. Activated coagulation factors such as tissue factor and VIIa complex and factor Xa activate protease-activated receptor 2 (PAR2). PAR2 promotes cytokine production through mitogen-activated protein kinase or nuclear factor kappa B signaling, and previous reports demonstrated that inhibition of PAR2 alleviated kidney injuries such as diabetic kidney disease and renal fibrosis in animal models. However, the involvement of PAR2 in the pathogenesis of SLE remains unclear. We therefore administered a selective PAR2 peptide antagonist, FSLLRY-NH2, to SLE-prone 4-month-old MRL-Fas^lpr mice for 4 weeks. Treatment with FSLLRY-NH2 caused the significant increases in the glomerular mesangial proliferation, glomerular deposition of both immunoglobulin G and complement factor C3d, and glomerular infiltration of Mac2-positive macrophages and CD3-positive T cells, compared with MRL-Fas^lpr mice treated with saline. In addition, the treatment with the PAR2 antagonist increased renal expression levels of tumor necrosis factor-α (Tnfa) and monocyte chemoattractant protein 1 (Mcp1) mRNA. Collectively, these results suggest that inhibition of PAR2 may increase the severity of inflammation in lupus nephritis; namely, opposite to previous observations, PAR2 has anti-inflammatory properties. We propose that activation of PAR2 could serve as a potential therapeutic option for patients with SLE.

Keywords —— coagulation factor; complement factor; cytokine; lupus nephritis; systemic lupus erythematosus

© 2019 Tohoku University Medical Press

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Tohoku J. Exp. Med., 2019, 249, 127-133

Correspondence: Nobuyuki Takahashi, M.D., Ph.D., Division of Clinical Pharmacology and Therapeutics, Tohoku University Graduate School of Pharmaceutical Sciences, 6-3 Aramaki Aoba, Aoba-ku, Sendai, Miyagi 980-8578, Japan.

e-mail: ntakaha@m.tohoku.ac.jp